Programmed death receptor Ligand 1 (PD-L1) is a ligand of programmed death receptor 1 (PD-1). PD-1 is primarily expressed on lymphocytes and has two ligands, PD-L1 and PD-L2. PD-L2 is not as common as PD-L1. PD-L1 is also known as cluster of differentiation 274 (CD274) or B7 homolog 1 (B7-H1) and is a 40 kDa type 1 transmembrane protein which is encoded by the CD274 gene. Both PD-L1 and PD-1 belong to immunoglobulin superfamily and consist of two extracellular Ig domains, an N-terminal V domain, and a C-terminal constant domain. The binding interface of PD-L1 to programmed death 1 (PD-1) and B7-1 (CD80) is on the IgV-like domain (Lin et al. (2008) PNAS 105:3011-3016). While PD-L1 contains a conserved short intracellular tail (about 30 amino acids), PD-1 contains two cytoplasmic tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T cell stimulation, PD-1 recruits the tyrosine phosphatase SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3 Zeta, PKC theta and ZAP70 that are involved in the CD3 T cell signaling cascade (Freeman et al. (2000) J Exp Med 192:1027-34; Latchman, et. al. (2001) Nat Immunol 2:261-8; Carter et al. (2002) Eur J Immunol 32:634-43).
PD-L1 is not only widely distributed on leukocytes and nonhematopoietic cells in lymphoid and nonlymphoid tissues, but also in various cancer cells. Clinical data suggest that high tumor expression of PD-L1 is associated with increased tumor aggressiveness and poorer prognosis. The formation of PD-1/PD-L1 complex transmits an inhibitory signal and negatively regulates T cell immune responses; it inhibits TCR-mediated T cell activation, cytokine production and T cell proliferation (Fife et al. (2011) Nature Immunology 10:1185-1193); induces exhaustion or anergy among cognate antigen-specific T cells (Hofmeyer et al. (2011) Journal of Biomedicine and Biotechnology 2011:1-9); promotes the differentiation of TH1 cells into Foxp3+ regulatory T cells (Armanath et al. (2011) Science TransMed 3:1-13; Francisco et al. (2009) J. Exp. Med. 206:3015-3029); and induces apoptosis of effctor T cells. Disruption of the PD-L1 gene leads to up-regulated T cell responses and the generation of self-reactive T cells (Latchman et al. (2004) PNAS 101:10691-10696). Antibody blockade of either PD-1 or PD-L1 leads to increased antitumor immunity (Iwai et al. (2002) PNAS 99:12293-12297).
Thus, there is an important role for the PD-1/PD-L1 pathway in controlling immune responses. Dysfunction of PD-1/PD-L1 signaling appears to be correlated with initiation and development of diseases such as cancer and viral infection. Analysis of knockout animals has led to the understanding that PD-1/PD-L1 functions mainly in inducing and regulating peripheral tolerance. Thus, therapeutic blockade of the PD-1/PD-L1 pathway would be helpful in overcoming immune tolerance and in the treatment of cancer or infection as well as in boosting immunity during vaccination (either prophylactic or therapeutic). There is a need in the art for improved methods for blocking the PD-1/PD-L1 pathway.